Ipso -nitration of calix[6]azacryptands: Intriguing effect of the small rim capping pattern on the large rim substitution selectivity

Article abstract of DOI:10.1021/jo300179h

The ipso-nitration of calix[6]arene-based molecular receptors is a important synthetic pathway for the elaboration of more sophisticated systems. This reaction has been studied for a variety of capped calixarenes, and a general trend for the regioselectiv

Full text of DOI:10.1021/jo300179h

Article
pubs.acs.org/joc
Ipso-Nitration of Calix[6]azacryptands: Intriguing Effect of the Small
Rim Capping Pattern on the Large Rim Substitution Selectivity
Manuel Lejeune,† Jean-Franco
̧
is Picron,† Alice Mattiuzzi,† Angelique Lascaux,† Stephane De Cesco,†
́
́
Andrea Brugnara,‡ Gregory Thiabaud,‡ Ulrich Darbost,§ David Coquiere,‡ Benoit Colasson,‡
̀
Olivia Reinaud,*,‡ and Ivan Jabin*,†
†Laboratoire de Chimie Organique, Universite
Belgium
́
Libre de Bruxelles (U.L.B.), avenue F. D. Roosevelt, 50 CP160/06, B-1050 Bruxelles,
Paris Descartes, 45 rue
́ ́
ulaire et Supramoleculaire, UMR-CNRS 5246, Universite Claude Bernard Lyon 1, CPE Lyon,
‡Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (CNRS UMR 8601), Universite
́
des Saints-Per
̀
es, 75006 Paris, France
§Institut de Chimie et Biochimie Molec
́
43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
S
* Supporting Information
ABSTRACT: The ipso-nitration of calix[6]arene-based mo-
lecular receptors is a important synthetic pathway for the
elaboration of more sophisticated systems. This reaction has
been studied for a variety of capped calixarenes, and a general
trend for the regioselective nitration of three aromatic units
out of six in moderate to high yield has been observed. This
selectivity is, in part, attributed to the electronic connection
between the protonated cap at the small rim and the reactive
sites at the large rim. In addition, this work highlights the fact
that subtle conformational properties can drastically influence
the outcome of this reaction.
protonated by a Bronsted acid, the phenol unit becomes
deactivated toward electrophilic reagents such as NO2 or
INTRODUCTION
■
+
Selective functionalization of macrocycles is a key issue. Indeed,
it allows grafting functions to cavity-based receptors.1
Compared to cucurbituryl2 and cyclodextrins,3 methodologies
for calixarenes have been largely developed.4 They are mainly
based on the interactions between the neighboring phenol
groups at the small rim. The hydrogen-bonding connections
and/or alkaline cation-binding ability allow directing of the
nucleophilic reactivity of the phenol units. Whereas this allowed
the development of various methods for the selective small rim
functionalization, strategies allowing the selective introduction
of functions at the large rim are basically restricted to (i)
removal of the tBu groups allowing the para-condensation of
acyl derivatives and (ii) ipso-substitution of the tBu-aromatic
unit with strong electrophilic reagents.4 Selectivity at the large
rim is an issue because of the poor communication between
ArH or ArtBu units with each other.
In this paper, we describe a successful strategy based on the
control of the large rim reactivity by the small rim substitution
pattern. Taking advantage of the methodologies developed for
the selective small rim functionalization, we highlighted the
possible tuning of the large rim reactivity toward electrophiles.
More precisely, we have shown that the substitution pattern at
the small rim by specific groups allows the differentiation of the
reactivity in the para-position of the aromatic phenolic groups.
When bearing in the β-position groups basic enough to be
SOCl+ generated in solution. This strategy was revealed to be
powerful enough to direct ipso as well as non-ipso electrophilic
substitution at the large rim by nitro5 and chlorosulfonyl6
groups toward the units that are not deactivated. Such a finding
has opened the route to the synthesis of a variety of calixarene
selectively functionalized at the large rim as schematized in
Figure 1 for calix[6]arene nitro derivatives (1).
This strategy allowed us to introduce a variety of functional
groups7 through, for example, a sequence of reduction,
diazotation, and Cu-catalyzed Huisgen 1,3-dipolar cyclo-
addition reactions giving rise to receptors endowed with
multipoint recognition properties,8 ditopic ligands for metal
ions,9 or water-soluble receptors.10 It is also interesting that the
substitution pattern at the large rim allows the size to be tuned
and the opening of the cone cavity to act as an endoreceptor.11
Wanting to apply this methodology to calix[6]azacryptands
(Figure 2),12 we found surprising and interesting results that
highlight the importance of conformational freedom/constrains
of the calix macrocycle on the reactivity of its aromatic units at
the large rim. The results reported here concern two uncapped
calix[6]arenes (1a,b) and three kinds of capped macrocycles,
Received: January 24, 2012
Published: March 19, 2012
© 2012 American Chemical Society
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Figure 1. Ipso-nitration of 1,3,5-trisubstitued calix[6]arenes. Inset: rationalization of the selectivity.
a
Scheme 1. Syntheses of the Calix[6]tren Derivatives 2
Figure 2. Calix[6]azacryptands and uncapped calix[6]arenes consid-
ered herein.
so-called tren (2),13 tube (3), and tmpa (4),14 that differ not
only by their functions but also, importantly, by their flexibility
(Figure 2).
a
For compounds b and d: (i) N(CH2CH2NHTs)3, Cs2CO3/K2CO3,
DMF, rt then 90 °C, 33%; (ii) (from 2c) PhSH, Na2CO3, DMF, 50
°C, 75%; (iii) AcCl, TEA, THF, −40 °C then rt, 98%.
RESULTS AND DISCUSSION
C3v symmetrical species, a broad and complicated NMR
spectrum was observed for 2d. However, this latter spectrum
exhibited a classical C3v-symmetrical NMR pattern at high
temperature (373 K) in C2D2Cl4.21 This temperature-depend-
ent behavior can be likely ascribed to the cis−trans isomerism of
the N-Ac groups.22 Note that, similar to 2c, the methoxy
groups of 2b possess a significant high-field shifted resonance
(δOMe = 2.28 ppm), indicating their self-inclusion into the
cavity.23
Ipso-Nitration Reactions of the Calix[6]arenes 1a,b,
2a−e, 3a,b, and 4. All of the ipso-nitration reactions were
performed under the same experimental conditions, i.e.,
dissolution of the calix[6]arene derivative in CH2Cl2 and
addition of a mixture of fuming nitric acid and glacial acetic acid
(1:1, v/v) at 0 °C. The reaction mixtures were then stirred at rt
and monitored by ESI mass spectrometry (ESI-MS) analysis
(Table 1).
■
Syntheses of the Starting Calix[6]arenes. Similar to the
known nosyl derivative 2c,15 the triply bridged calixarene 2b
was synthesized through a [1 + 1] macrocyclization reaction
under basic conditions between a tren derivative bearing
sulfonamido groups and the 1,3,5-tris-tosylcalix[6]arene 5
(Scheme 1). After flash chromatography on silica gel (FC),
pure calix[6]azacryptand 2b was obtained in 33% yield.16
Calix[6]arene 2d was obtained in 98% yield from the known
calix[6]tren 2a15 by reaction with acetyl chloride in the
presence of triethylamine (TEA). All of the other starting
calix[6]arenes, i.e., 1a,b, 2a,c,e, 3a,b, and 4, were prepared
according to previously reported procedures. In particular, 1a
was obtained through reduction of the corresponding tris-azido
derivative,17 2a and 3a through deprotection of the
corresponding nosyl derivatives 2c and 3b,18 2e through a [1
+ 1] macrocyclization between 1a and nitrilotriacetic acid,19
and 4 through a [1 + 1] macrocyclization between 1,3,5-tris-O-
methylated calix[6]arene and a tmpa derivative.20 It is
First, similarly to what was reported in the case of the tris-
aminocalix[6]arenes 1a and 3a, selective ipso-nitration of the
anisole units of 2a afforded the 1,3,5-tris-nitrated calix[6]arene
2aNO2 (Scheme 2 and Table 1, entries 1, 3, and 8). Thus, with
1
noteworthy to mention that, while the H NMR spectra of
2a−c and 2e in CDCl3 display sharp signals characteristic of a
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1b gave the hexa-nitrated calixarene 1bNO2 as the sole isolable
reaction product (Scheme 3 and Table 1, entries 2 and 9).
However, ipso-nitration of the tosyl and nosyl derivatives of
calix[6]tren 2b and 2c was revealed to be highly selective, and
the resulting 1,3,5-tris-nitrated calix[6]arenes 2bNO2 and 2cNO2
were isolated in high yield (Scheme 3 and Table 1, entries 4
and 5).
Table 1. Ipso-Nitration Reactions of Calix[6]arenes 1a,b,
2a−e, 3a,b, and 4
starting
material
selective nitration of
the anisole units
time
(h)
isolated
yield (%)
entry
product
1 (lit.)
1a
1b
2a
2b
2c
2d
2e
3a
3b
4
yes
no
1aNO2
1bNO2
2aNO2
2bNO2
2cNO2
2dNO2
2eNO2
3aNO2
3bNO2
4NO2
1
55
44
2
4
4
4
4
8
4
4
4
a
3
yes
yes
yes
yes
63
Similarly to 2b and 2c, the tren based tris-amido calix[6]-
arene 2d led selectively to the corresponding 1,3,5-tris-nitrated
derivative 2dNO2 (Scheme 4 and Table 1, entry 6). In strong
contrast, the closely related tris-amido calix[6]arene 2e afforded
a mixture of penta- and hexa-nitrated compounds (Scheme 4
and Table 1, entry 7), which were clearly identified by ESI-MS
analysis but revealed to be difficult to separate by FC.24
Finally, calix[6]tmpa 4 also underwent a selective trans-
formation to provide compound 4NO2 (Scheme 4 and Table 1,
entry 10). However, the nitration process revealed to be much
slower: after 4 h of reaction, a mixture of di- and trinitrated
products was obtained under conditions where the other calix-
substrates were fully tris-nitrated.5 After 20 h, traces of tetra-
nitrated product were detected in the crude reaction mixture
(analyzed by ESI-MS), whereas 4NO2 became the very major
product (>90%). A detailed kinetic analysis of the nitration of
calix[6]tmpa, monitored by ESI-MS, is shown in the
Supporting Information. The data were fitted according to a
three-step mechanism assuming that each step follows a pseudo
first order rate law vs the substrate calixarene 4 derivative,
according to
4
93
95
83
5
6
b
7
no
a
8 (lit.)
yes
35
c
9
no
d
10
yes
ca. 20
ca. 90
a
b
Overall yield for the three-step sequence (see the text). A mixture of
penta- and hexanitrated products was observed by ESI-MS analysis of
c
the crude material. A mixture of polynitrated products was observed
d
by ESI-MS analysis of the crude material. The isolated solid contains
ca. 5% of a mixture of di- and tetranitrated product; see the Supporting
Information.
all these polyamino calix[6]arenes, the selectivity of the
nitration reaction is in good agreement with the model
displayed in Figure 1, i.e., a deactivation of the aromatic units
bearing the amino arms through protonation of the primary or
secondary amino groups. Note that a sequence involving the
synthesis/purification/deprotection of a tris-carbamate deriva-
tive was necessary in order to isolate pure 2aNO2. The relatively
moderate yields observed for the nitration of calix[6]arenes 1a,
2a, and 3a are not due to a lack of selectivity (no other nitrated
products were observed by ESI-MS analysis and no other
products could be isolated) and are attributable to the
competitive degradation of the primary and secondary amino
arms that are quite sensitive to oxidizing media.
k1
k2
k3
4 → mono‐nitrated 4 → di‐nitrated 4 → tris‐nitrated 4 = 4NO2
where ki stands for the pseudo-rate constant of step (i). The
fitted data clearly show that the nitration process becomes
slower as the calix[6]tmpa is nitrated: k1 = 4.0k2 and k2 = 7.5k3.
However, the decrease in the ki values (k1 > k2 > k3) is more
important than that corresponding to a pure statistical
correction (k1 = 3/2k2; k2 = 2k3) due to the variation of the
number of available tBu-anisole sites. This indicates that the
nitration of the ith anisol induces a structural/electronic
Conversely, no selectivity was a priori expected with the
derivatives 1b, 2b−c, and 3b since, according to their pKa
values, their sulfonamido groups should not be protonated
under the reaction conditions. As anticipated, nitration of 3b
led to a complicated mixture of poly-nitrated compounds and
a
Scheme 2. Ipso-Nitration Reactions of Calix[6]arenes 1a, 2a, and 3a
a
Key: (i) HNO3/AcOH (1:1, v/v), CH2Cl2, 0 °C then rt; (ii) Boc2O, TEA, THF, 0 °C then rt; (iii) TFA, CH2Cl2, rt.
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a
Scheme 3. Ipso-Nitration Reactions of Sulfonamido Calix[6]arenes b and c
a
Key: (i) HNO3/AcOH (1:1, v/v), CH2Cl2, 0 °C then rt.
a
Scheme 4. Ipso-Nitration Reactions of Tris-amido Calix[6]arenes 2d and 2e and Calix[6]TMPA 4
a
Key: (i) HNO3/AcOH (1:1, v/v), CH2Cl2, 0 °C then rt.
modification leading to an intrinsic decrease of the reactivity of
the (3 − i) remaining positions. These observations suggest
that the tmpa cap imposes constrains that are different from
both the tris-methylpyridyl (type 1) and tren (type 2) cases,
which are both much more selective and much more reactive.
NMR Characterization of New 1,3,5-Tris-nitrated
Calix[6]arenes 2aNO2−dNO2 and 4NO2. The 1H NMR spectra
of 2aNO2−dNO2 and 4NO2 in CDCl3 are characteristic of C3v
symmetrical species and all signals were assigned by extensive
2D NMR analyses.25 First, in all cases, the selective ipso-
substitution of three alternating tBu groups was confirmed by
the presence of a single resonance that integrates for 27
protons. Moreover, it was possible to deduce from the
following NMR data that the nitro groups are situated on the
anisole units: (i) the tBu and methoxy groups of compounds
2bNO2, 2cNO2 and 4NO2 display high-field chemical shifts (i.e.,
δtBu = 1.02, 1.09, and 0.96 ppm; δOMe = 2.65, 2.77, and 2.67
ppm, respectively), suggesting that all these groups are directed
toward the inside of the cavity and, as a result, are not
connected to the same phenolic units. A similar conclusion can
be made for 2aNO2 and 2dNO2 with the difference that their
OMe and tBu groups are turned toward the outside of the
cavity (δtBu = 1.36 and 1.19 ppm; δOMe = ca. 3.7 and 3.6 ppm,
respectively). (ii) HMBC NMR experiments undertaken with
compounds 2bNO2 and 2cNO2 show a series of cross-peaks
indicating that the methoxy groups are located on the aromatic
units bearing the nitro groups.
Thus, these extensive NMR studies clearly confirm the
structure of the 1,3,5-tris-nitrated calix[6]arenes 2aNO2-dNO2
and 4NO2
.
Selectivity of the Nitration Process. This study has
highlighted surprising differences in the reactivity of the calix
derivatives vs nitration when they are capped or uncapped.
(1) The N-sulfonamido and N-acetamido calix[6]tren
derivatives (2b,c and 2d, respectively) are nitrated with
remarkable regioselectivity, which allows the efficient synthesis
of their tris-nitro derivatives with high yields, no chromatog-
raphy being required for their isolation as pure compounds.
This represents an interesting alternative to the direct nitration
of the unprotected tren derivative 2a that gives rise to low and
hardly reproducible yields.
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Figure 3. 1H NMR spectra (300 MHz, 295 K) in CD3CN of (a) 2aNO2·Zn2+⊃CD3CN obtained upon the addition of 1 equiv of Zn(ClO4)2·6H2O to
2aNO2; (b) 2aNO2·4H+⊃CD3CN obtained after the subsequent addition of TFA. Inset: High-field region of the 1H NMR spectrum of
2aNO2·Zn2+⊃OctNH2 obtained after addition of few equivalents of OctNH2 to 2aNO2·Zn2+⊃CD3CN. Key: w, water; s, residual solvent; *, residual
grease.
(2) In strong contrast, their uncapped and tube analogues
(1b and 3b) or the related trenamide derivative (2e) do not
display any selectivity vs the nitration process. A plausible
explanation for this surprising difference in selectivity possibly
lies in the much higher conformational rigidity of the aromatic
cavity of 2b and 2c induced by the covalent tren cap presenting
tris-substituted nitrogen connections. An important steric
crowding at the level of these nitrogen connections may
disfavor the local planar conformation required for the
conjugation between the nitrogen lone pairs and the
sulfonamido/acetamido groups of 2b,c and 2d. As a result,
the nitrogen atoms may be basic enough to be protonated
under the strongly acidic conditions of the nitration reaction,
leading to the efficient deactivation of the corresponding
aromatic units linked to the tren cap.26
the alternation of the aromatic walls. Indeed, the more rigid
tmpa cap (compared to a tren derivative), made out of cyclic
and planar pyridine residues, forces the connected aromatic
units to adopt an in-position relative to the anisole units, as
20
1
shown by XRD analysis and H NMR spectroscopy. Once
nitrated, the less bulky anisole walls tend to flip more toward an
in-position at the large rim as shown by the outward movement
of the methoxy groups (δOMe = 2.67 vs 2.53 ppm for 4NO2 and
4, respectively). Conversely, the remaining tBu-aryl units flip
toward an out-position (δtBu = 0.96 vs 0.86 ppm for 4NO2 and 4,
respectively). The rocking movement of the aromatic walls in
alternate position, initiated by the replacement of the bulky tBu
groups by nitro substituents at the sterical constrained large
rim, may well lead, progressively, i.e., as the nitration proceeds,
to the decrease of the spatial accessibility of the remaining tBu-
substituted anisol units. The consequent decrease of their
reactivity would then explain the anticooperativity of the
substitution process.
(3) The tmpa case also raises questions. First, the nitration
process is not as regioselective as for its uncapped tris-
methylpyridyl analogue (Figure 1, compound 1) or more
flexible tren-capped related compounds 2. This may be
attributed to the difficult polyprotonation of the rigid cap as
reported previously.21 Indeed, the calix macrocycle imposes a
geometry where the nitrogen atoms of the pyridyl units face
each other, which make difficult the polyprotonation of the
tmpa cap, in spite of a strong propensity for a first protonation
event. As a result, the deactivating effect of the connected
All these observations highlight the fact that selectivity is
actually the result of privileged orientations adopted by the
different aromatic units, which, in turn, depend on the
conformational properties of the cap as a slight structural
alteration at the level of the cap or the calix substitution pattern
can strongly influence a reaction occurring at the level of the
large rim, both in terms of reactivity (rate) and regioselectivity.
Evaluation of the Host−guest Properties of the Tris-
nitro Calix[6]cryptands. In order to test whether or not the
tris-nitrated calix[6]azacryptands still display interesting com-
plexation properties, preliminary NMR binding studies were
+
aromatic units toward the electrophilic attack of NO2 due to
the withdrawing effect of the protonated pyridyl residues is not
as efficient as for the related open analog (type 1) compound
or more flexible nonaromatic tren derivatives (type 2). This
may explain the lower selectivity in the nitration reaction for
the tmpa capped 4 compound relative to substrates of type 1
and 2.
(4) The second question raised by tmpa derivative 4 is
related to the relatively slow reaction rate of the nitration
compared to the other calix-substrates and its anticooperative
behavior for the polynitration. The structural features that
differentiate the tmpa-capped calixarenes from the other capped
derivatives are not only a much more rigid calix core but also
achieved with the open calix[6]azacryptand 2aNO2.
27 The host−
guest properties of the other new calix[6]azacryptand that can
bind metal ions, i.e., 4NO2, will be published elsewhere. First,
upon addition of 1 equiv of Zn(ClO4)2·6H2O to a CD3CN
solution of 2aNO2, a completely distinct but complicated NMR
pattern was obtained. This NMR spectrum is characteristic of a
nonsymmetrical C1-calixarene species: three singlets for the tBu
as well as for the OMe and twelve singlets for the ArH are
indeed apparent (Figure 3a). By analogy with the results
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obtained with 2a,28 this NMR profile clearly corresponds to the
dicationic complex 2aNO2·Zn2+⊃CD3CN with an intracavity
acetonitrile molecule coordinated to the metal center.
Compared to the free ligand 2aNO2, the OMe signals of the
complex are downfield shifted (δOMe > ca. 3.9 ppm), indicating
that these groups have been expelled from the cavity by the
coordinated acetonitrile molecule. Similarly to the parent
c o m p l e x 2 a · Z n 2 + ⊃ C D 3 C N , t h e c h i r a l i t y o f
2aNO2·Zn2+⊃CD3CN arises from the heterochirality of the
three NH stereocenters.29 As expected, the coordinated solvent
molecule was found to be exchangeable. For example, the
addition of a few equivalents of primary amines (i.e., PrNH2,
OctNH2) led to their intracavity binding as testified by the
presence of high-field signals below 0 ppm assigned to their
alkyl chain (inset Figure 3). Finally, upon the addition of an
excess of trifluoroacetic acid (TFA) to 2aNO2·Zn2+⊃CD3CN in
CD3CN, a well-resolved and simpler C3v-symmetrical NMR
pattern was obtained (Figure 3b). Again, by analogy with what
was observed with 2a, it is possible to deduce that this NMR
spectrum corresponds to the tetracationic host−guest complex
2aNO2·4H+⊃CD3CN.30 All these results show that the
remarkably versatile host−guest properties of this class of
receptors are preserved.
calix[6]arenes 1a,b, 1aNO2, 2a, 2c, 2e, 3a,b, 3aNO2, and 4, were
prepared according to literature procedures (see the text).
X6Me3tren(Ts)3 (2b). Cs2CO3 (0.048 g, 0.149 mmol) and K2CO3
(0.120 g, 0.868 mmol) were added to a solution of 1,3,5-tris-
tosylcalix[6]arene 5 (0.455 g, 0.282 mmol) in anhydrous DMF (10
mL) at room temperature. The resulting mixture was vigorously
stirred, and a solution of N(CH2CH2NHTs)3 (0.188 g, 0.308 mmol)
was slowly added at room temperature. After being stirred for 2 h, the
reaction mixture was heated at 90 °C for 24 h. The solvent was
evaporated under reduced pressure. The residue was dissolved in
CH2Cl2 (40 mL) and washed with distilled water (20 mL). The
organic solvent was evaporated under reduced pressure, and the crude
product was purified by flash chromatography [CH2Cl2 then CH2Cl2/
EtOAc (95:5, v/v)], giving 2b as a pale yellow solid. Yield: 33% (0.173
g, 0.101 mmol). Mp = 193−194 °C dec. 1H NMR (300 MHz, CDCl3,
298 K): δ = 7.83 (d, 6H, ArHTs, J = 8.3 Hz), 7.24 (s, 6H, ArH), 7.11
(d, 6H, ArHTs, J = 8.1 Hz), 6.83 (s, 6H, ArH), 4.29 (d, 6H, ArCH2ax, J
= 14.7 Hz), 4.06 (t, 6H, OCH2CH2N, J = 4.3 Hz), 3.86 (t, 6H,
OCH2CH2N, J = 4.6 Hz), 3.76 (t, 6H, CH2NCH2CH2N, J = 7.8 Hz),
3.08 (d, 6H, ArCH2eq, J = 14.7 Hz), 2.97 (t, 6H, CH2NCH2CH2N, J =
8.2 Hz), 2.28 (s, 9H, OCH3), 2.23 (s, 9H, CH3Ts), 1.37 (s, 27H, tBu),
0.84 (s, 27H, tBu) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ =
154.6, 150.2, 146.3, 146.0, 143.2, 137.9, 133.7, 133.1, 130.0, 127.8,
127.3, 123.8, 72.6, 61.0, 54.9, 49.1, 48.9, 34.4, 34.2, 31.8, 31.1, 28.8,
21.6 ppm. HRMS (ESI+): calcd for C102H133N4O12S3 [M + H]+
1701.9077, found 1701.9084.
X6Me3tren(acetyl)3 (2d). Anhydrous TEA (0.32 mL, 2.26 mmol)
was added to a solution of calix[6]tren 2a (0.312 g, 0.251 mmol) in
THF (25 mL) at −40 °C. After 5 min, freshly distilled acetyl chloride
(0.16 mL, 2.26 mmol) was added. A white precipate appeared, and the
reaction mixture was stirred at room temperature for 16 h. The
mixture was then filtered off in order to remove the ammonium salt.
The solvent was evaporated to dryness affording 2d as a pale yellow
solid. Yield: 98% (0.338 g, 0.25 mmol). Mp = 213−215 °C dec. IR
CONCLUSION
■
We have shown that the selective ipso-nitration reaction of
calix[6]arenes can be extended to calix[6]azacryptands. Indeed,
the introduction of three nitro groups in alternate positions has
been achieved in high yields with several calix[6]tren
derivatives and calix[6]tmpa, compounds that are widely used
as molecular receptors for metal ions, neutral molecules, and
ammonium ions. As previously reported, the results show the
drastic influence that the nature of the substituents at the small
rim has on the nitration reactions taking place at the large rim.
However, this work also highlights that the electronic
connection between the two rims is not the only factor
influencing the selectivity and that the conformational proper-
ties of the small rim part can also orient the selectivity of the
ipso-nitration and influence the reaction rate. Finally,
preliminary binding studies have shown that the complexation
properties of the tris-nitrated calix[6]tren are preserved despite
a more widely open cavity. This work opens interesting
perspectives for the design of a new generation of calix[6]-
azacryptands decorated at the large rim with various functional
groups. In this regard, the selective introduction of water-
soluble or ion binding groups is currently being explored in our
laboratories.
1
(KBr): ν = 1652 (CO) cm−1. H NMR (300 MHz, C2D2Cl4, 373
K): δ = 7.23 (s, 6H, ArH), 6.99 (bs, 6H, ArH), 4.60 (d, 6H, ArCH2ax, J
= 15.1 Hz), 4.25 (bs, 6H, OCH2CH2N), 3.91 (m, 15H, OCH2CH2N +
OCH3), 3.43 (d, 6H, ArCH2eq, J = 15.0 Hz), 2.94 (bs, 6H,
CH2NCH2CH2N), 2.63 (bs, 6H, CH2NCH2CH2N), 2.22 (s, 9H,
C(O)CH3), 1.35 (s, 27H, tBu), 0.99 (s, 27H, tBu) ppm. HRMS (ESI
+): calcd for C87H121N4O9 [M + H]+ 1365.9128, found 1365.9122.
Due to the cis−trans isomerism of the N-Ac groups (see the text), a
complex and uninterpretable 13C NMR (100 MHz, CDCl3, 298K)
spectrum was obtained for 2d (see the Supporting Information).
(NO2)3X6Me3tren (2aNO2). According to the procedure described for
2cNO2, 2a (0.223 g, 0.179 mmol) was reacted with a HNO3/AcOH
solution (2.20 mL, 1:1, v/v) in CH2Cl2 (20 mL) (reaction time: 4 h).
After workup, compound 2aNO2 was isolated as an orange solid (0.238
g, 0.197 mmol). This residue was then solubilized in THF (19 mL),
and TEA (0.22 mL, 1.57 mmol) was added. After the mixture was
cooled at 0 °C, Boc2O (0.257 g, 1.18 mmol) was added and the
resulting mixture stirred under argon at room temperature for 16 h.
The solvent was removed under reduced pressure, the residue was
dissolved in CH2Cl2, and the organic layer was washed with water. The
solvent was then removed under reduced pressure, and the residue was
purified by flash chromatography [CH2Cl2/AcOEt (8:2)] to give
(NO2)3X6Me3tren(N-Boc)3 2′aNO2 as a white solid. Yield: 63% (0.170
mg, 0.112 mmol). To a solution of 2′aNO2 (0.033 g, 0.022 mmol) in
CH2Cl2 (1.5 mL) was added dropwise 0.2 mL of TFA (2.3 mmol).
The mixture was then stirred at room temperature for 16 h. The
solvent was removed in vacuo, and the residue was dissolved in
CH2Cl2 (10 mL). The organic solution was washed with a NaOH
solution (1 M). The aqueous layer was extracted with CH2Cl2 (2 × 10
mL). The organic layers were combined and the solvent removed in
vacuo to obtain 2aNO2 in quantitative yield (0.027 g, 0.022 mmol). It is
noteworthy that the compound 2aNO2 revealed to be quite unstable
and thus difficult to purify and to store. Hopefully, full characterization
of the carbamate derivative 2′aNO2 was successfully achieved.
EXPERIMENTAL SECTION
■
All experiments were performed under argon. Solvents were dried by
conventional methods and distilled immediately prior to use. Routine
1H NMR spectra were recorded at 200, 300, or 600 MHz. 13C NMR
spectra were recorded at 100,75, or 62.5 MHz. NMR spectra were
referenced to residual solvents. 2D NMR spectra (COSY, HSQC,
HMBC) were recorded to complete signal assignments. Multiplicity is
indicated as follows: s (singlet), d (doublet), t (triplet), m (multiplet),
dd (doublet of doublet), bs (broad singlet). Electrospray ionization
(ESI) mass spectra were recorded with an ESI-MS apparatus equipped
with an ion-trap using the following settings: Flow rate: 10 μL·min−1,
spray voltage: 5 kV, capillary temperature: 160 °C, capillary voltage:
−15 V, tube lens offset voltage: −30 V. Melting points (mp) are
uncorrected. N(CH2CH2NHTs)3,31 5,11,17,23,29,35-hexa-tert-butyl-
37,39,41-trimethoxy-38,40,42-tris(2-tosylethoxy)calix[6]arene 5,
2′aNO2. Mp = 240−242 °C dec. IR (CHCl3): ν = 1681 (CO),
1
1522 (NO2) cm−1. H NMR (200 MHz, CDCl3, 298 K): δ = 7.95−
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Article
7.65 (m, 6H, ArH), 7.09 (bs, 6H, ArH), 4.53 (d, 6H, ArCH2ax, J = 14.6
v) in CH2Cl2 (8 mL) (reaction time: 4 h). The crude product was
purified by flash chromatography [CH2Cl2, CH2Cl2/EtOAc (95:5, v/
v), CH2Cl2/EtOAc (90:10, v/v), CH2Cl2/MeOH (95:5, v/v) then
CH2Cl2/MeOH (70:30, v/v)], giving 1bNO2 as an orange solid. Yield:
44% (43 mg, 0.026 mmol). Mp = 182−184 °C dec. IR (KBr): ν =
1540 (NO2), 1522 (NO2) cm−1. 1H NMR (300 MHz, DMSO-d6, 363
K): δ = 8.09−7.75 (m, 18H, ArH + ArHNs), 7.40 (bs, 6H, ArH), 4.22
(m, 12H, ArCH2ax + ArCH2eq), 4.08 (t, 6H, OCH2CH2N, J = 6.0 Hz),
3.55 (s, 9H, OCH3), 3.42 (m, 6H, OCH2CH2N) ppm. HRMS (ESI+):
calcd for C69H60N12O30NaS3 [M + Na]+ 1655.2603, found 1655.2598.
Note that the 13C NMR (100 MHz, DMSO-d6, 298 K) spectrum of
1bNO2 was also recorded; however, most of the peaks were too broad
to be apparent (see the Supporting Information).
eq
Hz), 4.04 (bs, 6H, OCH2CH2N), 3.73−3.35 (m, 21H, ArCH2
,
OCH3 + OCH2CH2N), 3.10−2.60 (m, 12H, CH2NCH2CH2N), 1.45−
1.38 (m, 27H, tBuBoc), 1.14 (s, 27H, tBu) ppm. 13C NMR (75 MHz,
CDCl3, 298K): δ = 28.5, 28.6, 29.3, 29.6, 31.4, 34.5, 47.7, 47.9, 49.9,
54.5, 61.1, 61.2, 77.4, 79.9, 124.8, 125.2, 125.4, 125.8, 131.9, 135.7,
143.4, 148.0(7), 148.1(3), 151.0, 151.3, 155.2, 155.5, 162.9 ppm.
C85H121N7O21·3H2O (1575.86): C, 64.64; H, 7.56; N, 6.28. Found: C,
64.48; H, 7.56; N, 6.28.
2aNO2. Mp = 215−216 °C dec. IR (CHCl3): ν = 1522 (NO2) cm−1.
1H NMR (CDCl3, 200 MHz, 298 K): δ = 7.36 (s, 6H, ArH), 7.23 (s,
6H, ArH), 4.29 (d, 6H, ArCH2ax, J = 16.4 Hz), 3.80−3.60 (m, 15H,
OCH3 + ArCH2eq), 3.43 (bs, 6H, OCH2CH2N), 2.51 (bs, 6H,
OCH2CH2N), 2.40 (bs, 6H, CH2NCH2CH2N), 2.24 (bs, 6H,
CH2NCH2CH2N), 1.36 (s, 27H, tBu) ppm. 13C NMR (CDCl3, 50
MHz, 298 K): δ = 160.5, 154.0, 147.6, 144.1, 135.6, 131.3, 128.5,
122.6, 73.5, 60.7, 54.0, 48.2, 34.5, 31.6 ppm.
(NO2)3X6Me3tmpa (4NO2). According to the procedure described for
2cNO2, 4 (0.250 g, 0.187 mmol) was reacted with a HNO3/AcOH
solution (1.6 mL, 1:1, v/v) in CH2Cl2 (25 mL) (reaction time: ca. 20−
23 h). Then, a solution of NaOH (3M) was added at 0 °C. The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The organic
layer was dried with Na2SO4, filtered, and evaporated to dryness. A
brown/yellow solid is obtained (0.230 g), containing 4NO2 as a major
compound (ca. 95%) together with variable amounts of dinitrated 4
product (0−8%) and tetra-nitrated 4 product (2−7%). Yield in 4NO2
(as isolated): ca. 90% (0.17 mmol) mp =202−204 °C. IR (KBr): ν =
(NO2)3X6Me3tren(Ts)3 (2bNO2). According to the procedure
described for 2cNO2, 2b (0.163 g, 0.096 mmol) was reacted with a
mixture of HNO3/AcOH (2 mL, 1:1, v/v) in CH2Cl2 (16 mL)
(reaction time: 4 h), giving 2bNO2 as an orange solid. Yield: 93%
(0.157 mg, 0.089 mmol). Mp = 176−178 °C dec. IR (KBr): ν = 1525
1
(NO2) cm−1. H NMR (600 MHz, CDCl3, 298 K): δ = 7.96 (s, 6H,
1
1522 (NO2) cm−1. H NMR (250 MHz, CDCl3, 300 K): δ = 8.10 (s,
ArH), 7.80 (d, 6H, ArHTs, J = 7.8 Hz), 7.18 (d, 6H, ArHTs, J = 7.8 Hz),
6.93 (s, 6H, ArH), 4.38 (d, 6H, ArCH2ax, J = 14.9 Hz), 4.03 (t, 6H,
OCH2CH2N, J = 4.2 Hz), 3.74 (t, 6H, OCH2CH2N, J = 4.5 Hz), 3.62
(t, 6H, CH2NCH2CH2N, J = 8.0 Hz), 3.33 (d, 6H, ArCH2eq, J = 15.0
Hz), 2.86 (t, 6H, CH2NCH2CH2N, J = 8.1 Hz), 2.65 (s, 9H, OCH3),
2.34 (s, 9H, CH3Ts), 1.02 (s, 27H, tBu) ppm. 13C NMR (75 MHz,
CDCl3, 298 K): δ = 162.8, 150.6, 148.0, 143.6, 143.4, 137.7, 135.7,
132.2, 130.0, 127.3, 125.7, 125.0, 73.8, 61.4, 53.5, 49.0, 48.5, 34.5, 31.3,
29.5, 21.6 ppm. HRMS (ESI+): calcd for C90H106N7O18S3 [M + H]+
1668.6757, found 1668.6725.
6H, ArHNO2), 7.62 (m, 3H, ArHpy), 7.52 (m, 3H, ArHpy), 7.12 (d, 3H,
ArHpy, J = 7 Hz), 6.83 (s, 6H, ArHtBu), 5.42 (s, 6H, PyCH2O), 4.45 (d,
6H, ArCH2ax, J = 15 Hz), 3.69 (s, 6H, PyCH2N), 3.60 (d, 6H,
ArCH2eq, J = 15 Hz), 2.67 (s, 9H, OCH3), 0.96 (s, 27H, tBu) ppm. 13
C
NMR (62.5 MHz, CDCl3, 300 K): δ = 163.83, 158.25, 157.87, 152.08,
147.20, 143.36, 136.94, 136,05, 132.92, 126.47, 125.13, 122.32, 118.19,
75.05, 61.98, 60.23, 34.33, 31.54, 31.29 ppm. HRMS (ESI+): calcd for
C78H82N7O12 [M + H]+ 1308.6021, found 1308.6058.
(NO2)3X6Me3tren(Ns)3 (2cNO2). To a solution of 2c (0.326 g, 0.182
mmol) in CH2Cl2 (32 mL) was added dropwise a mixture of HNO3/
AcOH (4 mL, 1:1, v/v) at 0 °C under argon. After addition, the
resulting solution was warmed up to room temperature and stirred for
4 h. The reaction mixture was then poured into an aqueous ammonia
solution (2.5%, 60 mL), and the aqueous layer was extracted with
CH2Cl2 (2 × 25 mL). The organic layers were combined, washed with
water (2 × 50 mL), and dried over Na2SO4. The yellow solution was
filtered, and the solvent was then removed in vacuo to afford 2cNO2 as
an orange solid. Yield: 95% (0.305 g, 0.173 mmol). Mp = 188−190 °C
ASSOCIATED CONTENT
■
S
* Supporting Information
1D, 2D NMR spectra of all new compounds, variable-
temperature 1H NMR studies of 2d, 2dNO2, and 4NO2
(monoprotonated by TFA), kinetic studies of the nitration of
4, and ESI-MS spectrum of 4NO2. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
1
dec. IR (KBr): ν = 1547 (NO2), 1525 (NO2) cm−1. H NMR (300
■
Corresponding Author
MHz, CDCl3, 298 K): δ = 8.18 (dd, 3H, ArHNs, J = 1.0 Hz, J = 8.1
Hz), 7.83 (s, 6H, ArH), 7.65−7.48 (m, 9H, ArHNs), 7.02 (s, 6H, ArH),
4.41 (d, 6H, ArCH2ax, J = 14.8 Hz), 4.08 (bs, 6H, OCH2CH2N), 3.91
(bs, 6H, OCH2CH2N), 3.79 (t, 6H, CH2NCH2CH2N, J = 7.8 Hz),
3.33 (d, 6H, ArCH2eq, J = 15.0 Hz), 2.82 (t, 6H, CH2NCH2CH2N, J =
7.8 Hz), 2.77 (s, 9H, OCH3), 1.09 (s, 27H, tBu) ppm. 13C NMR (75
MHz, CDCl3, 298 K): δ = 162.8, 150.7, 148.3, 148.0, 143.4, 135.6,
133.9, 133.7, 132.2, 131.9, 131.0, 125.5, 125.3, 124.1, 74.5, 61.4, 52.8,
48.6, 48.1, 34.5, 31.3, 29.6 ppm. HRMS (ESI+): calcd for
C87H96N10O24NaS3 [M + Na]+ 1783.5659, found 1783.5690.
*(I.J.) Tel: +32-2-650-35-37. Fax: +32-2-650-27-98. E-mail:
ijabin@ulb.ac.be. (O.R.) Tel: +33-1-42-86-21-83. Fax: +33-1-
42-86-83-87. E-mail: olivia.reinaud@parisdescartes.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Fonds pour la formation a
la Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.) (J.-
F.P. Ph.D. grant), the Fonds National pour la Recherche
Scientifique (FNRS) (FRFC program and A.M. Ph.D. grant),
and the ULB (A.L. Ph.D. grant). It was also supported by the
̀
(NO2)3X6Me3tren(acetyl)3 (2dNO2). According to the procedure
described for 2cNO2, 2d (0.321 g, 0.235 mmol) was reacted with a
mixture of HNO3/AcOH (3 mL, 1:1, v/v) in dry CH2Cl2 (20 mL)
(reaction time: 8 h). After workup, the crude product was triturated
with Et2O to isolate 2dNO2 as an orange solid. Yield: 83% (0.260 g,
0.195 mmol). Mp = 196−198 °C dec. IR (KBr): ν = 1648 (CO),
1525 (NO2) cm−1. 1H NMR (300 MHz, DMSO-d6, 373 K): δ = 7.63
CNRS (Institut de Chimie), the Minister
̀
e de l′Enseignement
Superieur et de la Recherche, the Agence Nationale pour la
́
(bs, 6H, ArHNO2), 7.19 (s, 6H, ArHtBu), 4.43 (d, 6H, ArCH2ax, J = 15.0
Recherche [Cavity-zyme(Cu) Project ANR-2010-BLAN-7141],
and the COST Action “Supramolecular Chemistry in Water”
(CM 1005).
eq
Hz), 3.93 (m, 6H, OCH2CH2N), 3.72−3.61 (m, 15H, ArCH2
+
OCH3), 3.49 (m, 6H, CH2N), 3.19 (m, 6H, CH2NCH2CH2N), 2.72
(m, 6H, CH2N), 2.02 (s, 9H, C(O)CH3),1.19 (s, 27 H, tBu) ppm.
HRMS (ESI+): calcd for C75H94N7O15 [M + H]+ 1332.6802, found
1332.6823.
REFERENCES
■
(NO2)6X6Me3tris(2-(2-nitrobenzenesulfonamide)ethoxy)
(1bNO2). Similarly to the procedure described for 2cNO2, 1b (0.101 g,
0.059 mmol) was reacted with a mixture HNO3/AcOH (1 mL, 1:1, v/
(1) Cram, D. J.; Cram, J. M. In Container Molecules and their Guests,
Vol. 4: Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.;
The Royal Society of Chemistry: Cambridge, 1994.
3844
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Article
(2) Lagona, J.; Muchophadyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Chem., Int. Ed. 2005, 44, 4844−4870.
(3) Special issue on cyclodextrins: Chem. Rev. 1998, 98, 1741−2076.
(4) Gutsche, C. D. In Calixarenes: An introduction, 2nd Ed.,
Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.; The
Royal Society of Chemistry: Cambridge, 2008.
(28) Darbost, U.; Zeng, X.; Rager, M.-N.; Giorgi, M.; Jabin, I.;
Reinaud, O. Eur. J. Inorg. Chem. 2004, 4371−4374.
(29) Such an asymmetry was clearly evidenced on an X-ray structure
of the parent complex 2a·Zn2+⊃CD3CN.
(30) Darbost, U.; Rager, M.-N.; Petit, S.; Jabin, I.; Reinaud, O. J. Am.
́ ̀
Chem. Soc. 2005, 127, 8517−8525. See also: Darbost, U.; Seneque, O.;
Li, Y.; Bertho, G.; Marrot, J.; Rager, M.-N.; Reinaud, O.; Jabin, I.
Chem.Eur. J. 2007, 13, 2078−2088.
(5) Redon, S.; Li, Y.; Reinaud, O. J. Org. Chem. 2003, 68, 7004−7008.
(6) Coquiere, D.; Cadeau, H.; Rondelez, Y.; Giorgi, M.; Reinaud, O.
̀
(31) Llioudis, C. A.; Tocher, D. A.; Steed, J. W. J. Am. Chem. Soc.
2004, 126, 12395−12402.
J. Org. Chem. 2006, 71, 4059−4065.
(7) Coquiere, D.; Le Gac, S.; Darbost, U.; Sen
Reinaud, O. Org. Biomol. Chem. 2009, 7, 2485−2500.
(8) Coquiere, D.; de la Lande, A.; Martí, S.; Parisel, O.; Prange,
Reinaud, O. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 10449−10454.
Coquiere, D.; de la Lande, A.; Parisel, O.; Prange, T.; Reinaud, O.
Chem.Eur. J. 2009, 15, 11912−11917.
(9) Colasson, B.; Save, M.; Milko, P.; Roihova,
̀
́ ̀
eque, O.; Jabin, I.;
̀
́
T.;
̀
́
́
J.; Schroder, D.;
̈
Reinaud, O. Org. Lett. 2007, 9, 4987−4990. Colasson, B.; Le Poul, N.;
Le Mest, Y.; Reinaud, O. J. Am. Chem. Soc. 2010, 132, 4393−4398.
(10) Bize, C.; Garrigues, J.-C.; Blanzat, M.; Rico-Lattes, I.; Bistri, O.;
Colasson, B.; Reinaud, O. Chem. Commun. 2010, 46, 586−588. Bistri,
O.; Colasson, B.; Reinaud, O. Chem. Sci. 2012, 3, 811−818.
(11) Coquier
6, 3930−3934.
(12) For leading references on calix[6]azacryptands, see: Izzet, G.;
Douziech, B.; Prange, T.; Tomas, A.; Jabin, I.; Le Mest, Y.; Reinaud, O.
Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 6831−6836. Izzet, G.; Zeitouny,
J.; Akdas-Killig, H.; Frapart, Y.; Menage, S.; Douziech, B.; Jabin, I.; Le
̀
e, D.; Marrot, J.; Reinaud, O. Org. Biomol. Chem. 2008,
́
́
Mest, Y.; Reinaud, O. J. Am. Chem. Soc. 2008, 9514−9523. Reinaud,
O.; Le Mest, Y.; Jabin, I. In Calixarenes in the Nanoworld; Vicens, J.,
Harrowfield, J., Eds.; Springer-Verlag: Dordrecht, 2006; Chapter 13,
pp 259−285. Darbost, U.; Giorgi, M.; Reinaud, O.; Jabin, I. J. Org.
Chem. 2004, 69, 4879−4884. Garrier, E.; Le Gac, S.; Jabin, I.
Tetrahedron: Asymmetry 2005, 16, 3767−3771. Le Gac, S.; Zeng, X.;
Girardot, C.; Jabin, I. J. Org. Chem. 2006, 71, 9233−9236. Le Gac, S.;
́
Menand, M.; Jabin, I. Org. Lett. 2008, 10, 5195−5198.
(13) Tren: tris(2-aminoethyl)amine.
(14) Tmpa: tris(2-pyridylmethyl)amine.
(15) Jabin, I.; Reinaud, O. J. Org. Chem. 2003, 68, 3416−3419.
(16) This yield is similar to what is reported in the case of 2c; i.e., the
reaction between the trinosyl derivative of tren and the 1,3,5-
tritosylcalix[6]arene 5.
́
(17) Menand, M.; Jabin, I. Org. Lett. 2009, 11, 673−676.
(18) For 3a, see: Le Gac, S.; Zeng, X.; Reinaud, O.; Jabin, I. J. Org.
Chem. 2005, 70, 1204−1210.
(19) Lascaux, A.; Le Gac, S.; Wouters, J.; Luhmer, M.; Jabin, I. Org.
Biomol. Chem. 2010, 8, 4607−4616.
̀ ́
(20) Zeng, X.; Coquiere, D.; Alenda, A.; Garrier, E.; Prange, T.; Li,
Y.; Reinaud, O.; Jabin, I. Chem.Eur. J. 2006, 12, 6393−6402.
(21) See the Supporting Information.
(22) La Planche, L. A.; Rogers, M. T. J. Am. Chem. Soc. 1963, 85,
3728−3730.
(23) It was shown through an HMBC experiment that the tBu
groups of the anisole units are directed toward the outside of the
cavity. Thus, the high-field shift of the OMe groups is clearly due to
their self-inclusion and not to their close proximity to the aromatic
units of the tosyl groups.
(24) Prolonged time reaction did not change the ratio of penta-
nitrated vs hexa-nitrated compounds. This may indicate that the hexa-
nitrated derivative can be only obtained from one of the two possible
penta-nitrated regioisomers.
(25) In the case of 2dNO2, the NMR spectrum had to be recorded at
high T (373 K) in DMSO-d6 in order to show a C3v symmetrical NMR
pattern. Again, this temperature-dependent behavior can be likely due
to the cis−trans isomerism of the N-Ac groups of 2dNO2
.
(26) It is noteworthy that a 1H NMR study of the protonation of the
sulfonamido derivative 2cNO2 was undertaken; unfortunately, only
broad and noninterpretable spectra were obtained.
(27) It is noteworthy that the compound 2aNO2 was revealed to be
quite unstable and thus difficult to purify and to store.
3845
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